Cardiovascular disease causes 34% of all deaths in the United States (AHA, 2010) and 17.6 million Americans suffer from coronary heart disease (CHD). Of these, 8.5 million experience myocardial infarction (AHA 2006). Older Americans are at high risk for CHDs. Improved outcomes will require limiting ischemia-reperfusion (I/R) injury to preserve the functional myocardium after MI. Endothelial cells of the heart are in close proximity to cardiomyocytes and essentially regulate myocyte function in pathophysiological conditions. Endothelial and myocyte apoptosis are significant contributors for myocardial infarction following I/R. Studies have shown that endothelial apoptosis precedes myocyte apoptosis in the heart in I/R. We have recently developed transgenic mice that are deficient in functional thioredoxin (dnTrx-Tg), an endogenous redox-active antioxidant protein. We have also generated mice that express higher levels of Trx (Trx-Tg). Using these mice with gain-of-function and loss-of-function of Trx, we discovered that aged Trx-Tg mice are protected against myocardial infarction in response to ischemia-reperfusion (I/R), whereas those deficient in Trx, like wild type, undergo extensive myocardial damage. Thus, we hypothesize that increased levels of Trx can afford protection against endothelial apoptosis. This hypothesis leads to the Specific Aims of this proposal: Aim 1 will determine the role of Trx in endothelial apoptosis due to NRG1[unreadable]/ErbB4 signaling;Aim 2 will explore potential mechanisms of these effects as it related to Nox4 activation, eNOS expression via VEGF;and Aim 3 will determine whether increased levels of Trx inhibit apoptosis signal regulating kinase (ASK1) in I/R that protects myocyte apoptosis. The outcomes of this project will contribute to our understanding of the protective role of thioredoxin in endothelial apoptosis, which may lead to novel endothelium-based approaches to treat myocardial infarction. PUBLIC HEALTH RELEVANCE: Older Americans are at high risk for heart diseases. For example, less than 1% of Americans under the age of 39 show symptoms of heart disease compared to 55% of American older than 40 (AHA 2010). Our proposal will test beneficial role of thioredoxin an endogenous protein on the death of heart cells and due to conditions similar to bypass surgery and, if successful, this project will lay foundation for the therapeutic development this protein for treatment of heart disease.